The present invention relates to the field of non-invasive assessment of vascular endothelial function and more particularly to methods using phase contrast magnetic imaging angiography to determine flow mediated dilation and wall shear stress rates in order to determine vascular endothelial function in a patient.
Vascular endothelial dysfunction has been found to be the earliest detectable occurrence in the development of atherosclerosis. Function of the vascular endothelium is affected by various factors including the presence of various substances such as oxidized low-density lipoprotein and nitric oxide, or by physical stimuli. Therefore, assessment of vascular physiology is important in detecting and tracking the development of early stage atherosclerosis. Additionally, it will also be crucial to studies in inflammation, stroke, hypertension and diabetes research, as well as additional complications affected by atherosclerosis.
Arterial smooth muscle relaxation is mediated by endothelial dependent mechanisms (Furchgott R F, Zawadski J V. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980;288:373.), which involve the release of nitric oxide (Palmer R, et al. Nitric oxide release accounts for the biologic activity of endothelium-derived relaxing factor. Nature. 1987;327:524-526.). In vitro, the primary hemodynamic determinant of endothelial release of nitric oxide and subsequent vasodilation is wall shear stress (WSS) (Koller A, Kaley G. Endothelial regulation of wall shear stress and blood flow in skeletal muscle microcirculation. Am J Physiol. 1991;260:H862-H868.; Koller A, et al. Role of shear stress and endothelial prostaglandins in flow- and viscosity-induced dilation of arterioles in vitro. Circ Res 1993;72:1276-1284.; Busse R, et al. Signal transduction in endothelium-dependent vasodilation. Eur Heart J. 1993; 14:Suppl I,2-9.; Busse R, Fleming I. Pulsatile stretch and shear stress: physical stimuli determining the production of endothelium-derived relaxing factors. Journal of Vascular Research. 1998;35:73-84.) Larger increases in non-pulsatile shear stress have been shown to produce greater increases in diameter of isolated arteries from rat skeletal muscle (Koller A, Kaley G. Endothelial regulation of wall shear stress and blood flow in skeletal muscle microcirculation. Am J Physiol. 1991;260:H862-H868.). However, the effects of pulsatile shear stress are different than those of constant shear stress (Ziegler T, et al. Influence of oscillatory and unidirectional flow environments on the expression of endothelin and nitric oxide synthase in cultured endothelial cells. Arterioscler Thromb Vasc Biol. 1998;18:686-692.; Malek A M, et al. Modulation by pathophysiological stimuli of the shear stress-induced up-regulation of endothelial nitric oxide expression in endothelial cells. Neurosurgery. 1999;45:334-344.).
In humans, reduced FMD, (flow-mediated dilation) in hypertension has been found to result from at least in part lower baseline systolic WSS (Khder Y, et al. Shear stress abnormalities contribute to endothelial dysfunction in hypertension but not in type II diabetes. J. Hypertens. 1998;16:1619-1625.). Conversely, an increase in blood flow following a brief period of skeletal muscle ischemia is accompanied by dilation of the conduit artery (Sinoway Li et al. Characteristics of flow-mediated brachial artery vasodilation in human subjects. Cir Res. 1989;64:32-42.; Celermajer D S, et al. Noninvasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet. 1992;340:1111.). Furthermore, increases in the magnitude or duration of hyperemia lead to increased vasodilation, while arterial diameter decreases during a low-flow state caused by distal arterial occlusion (Corretti M C, et al. Technical aspects of evaluating brachial artery vasodilation using high-frequency ultrasound. Am J Physiol. 1995;268:H1397-H1404.; Leeson P, et al. Non-invasive measurement of endothelial function: effect on brachial artery dilation of graded endothelial dependent and independent stimuli. Heart. 1997;78:22-27.). The relationship between WSS and arterial flow-mediated dilation (FMD) however, has not been established in humans.
Vascular physiology can be assessed, in part, through measurements of endothelial function. Changes in the diameter of an artery in response to a stimulus such as change in blood flow velocity through the artery (arterial wall shear stress, WSS) are indicative of endothelial function, known as flow mediated dilation (FMD). Endothelial function can be measured by inflating a blood pressure cuff around a subject""s arm and monitoring velocity of blood flowing through a brachial artery while measuring the artery""s diameter before, during and after the inflation of the cuff.
Ultrasound measurements of flow mediated dilation have been widely used to study endothelial function in patients with known cardiac risk factors with (Hoeks A P G, et al. Noninvasive determination of shear-rate distribution across the arterial lumen. Hypertension. 1995;26:26-33.; Levine G N, et al. Ascorbic acid reverses endothelial vasomotor dysfunction in patients with coronary artery disease. Circulation. 1996;93:210-214.; Vogel R A, et al. Changes in flow-mediated brachial artery vasoreactivity with lowering of desirable cholesterol levels in healthy middle-aged men. Am J Cardiol. 1996;77:37-40.; Motoyama T, et al. Endothelium-dependent vasodilation in the brachial artery is impaired in smokers: effect of vitamin C. Am J Physiol. 1997;273:H1644-H1650.; Plotnick G D, et al. Effect of antioxidant vitamins on the transient impairment of endothelial-dependent brachial artery vasoactivity following a single high-fat meal. JAMA. 1997;278:1682-1686.; Hornig B, et al. Vitamin C improves endothelial function of conduit arteries in patients with chronic heart failure. Circulation. 1998;97:363-368.; Neunteufl T, et al. Additional benefit of vitamin E supplementation to simvastatin therapy on vasoreactivity of the brachial artery of hypercholesterolemic men. J Am Coll Cardiol. 1998;32:711-716.; Chambers J C, et al. Demonstration of rapid onset vascular endothelial dysfunction after hyperhomocysteinemia: an effect reversible with vitamin C therapy. Circulation. 1999;99:1156-1160.) and without (Celermajer D S, et al. Noninvasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet. 1992;340:1111.; Celermajer D S, et al. Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults. Circulation. 1993;88:2149-2155.; Celermajer D S, et al. Passive smoking and impaired endothelium-dependent arterial dilation in healthy young adults. N Engl J Med. 1996;334:150-154.) intervention. However, there is considerable overlap in the arterial dilatory response between individuals with and without cardiac risk factors (Corretti M C, et al. Technical aspects of evaluating brachial artery vasodilation using high-frequency ultrasound. Am J Physiol. 1995;268:H 1397-H1404.; Celermajer D S, et al. Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults. Circulation. 1993;88:2149-2155.; Celermajer D S, et al. Passive smoking and impaired endothelium-dependent arterial dilation in healthy young adults. N Engl J Med. 1996;334:150-154.). This is in part because FMD is inversely related to baseline diameter (Celermajer D S, et al. Noninvasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet. 1992;340:1111.). There is evidence from the study of rat skeletal muscle arterioles that this inverse relationship may be due to an inverse relationship between baseline diameter and wall shear stress (Koller A, Kaley G. Endothelial regulation of wall shear stress and blood flow in skeletal muscle microcirculation. Am J Physiol. 1991;260:H862-H868.).
Current methods to assess endothelial function non-invasively use ultrasound to measure flow mediated dilation of a limb artery after release of a temporary occlusion of that limb. However, use of ultrasound poses problems for assessment of vascular endothelial function. In addition to those technical problems discussed above wherein there is significant overlap of readings between patient populations, ultrasound measurements may be poorly reproducible because the technique is highly operator dependent with regard to probe positioning. Additionally, although dilation may be measured additional measurements to determine shear stress stimulus by ultrasound can only be accomplished using sophisticated, non-standard, signal processing equipment.
It thus would be desirable to provide novel methods for the non-invasive assessment of vascular endothelial function which are more effective, and reliable than current ultrasound methods. It also would be desirable that the new methods would not be dependent on the testing administrator; would generate consistent results; and would be readily adaptable to use for regular diagnostic screening protocols.
The references discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention.
The present invention features improved methods for non-invasive assessment of vascular endothelial function. Preferred methods of the invention use phase contrast magnetic resonance imaging to obtain images of an artery which can then be used to determine measurements to assess vascular endothelial function.
One preferred method of assessing vascular endothelial function of a subject during hyperemic response comprises:
(a) using a magnetic resonance imaging scanner to obtain images;
(b) locating an artery using coronal scout images;
(c) positioning the subject, such that the artery is parallel to a magnet bore of the magnetic resonance imaging scanner and cross sectional images can be obtained;
(d) constricting the artery for a time period, whereby the artery is fully occluded;
(e) releasing the artery from occlusion;
(f) acquiring images of the artery prior to occlusion (at baseline), as well as during occlusion, and at time periods following release from occlusion;
(g) calculating indicators of vascular endothelial function: wall shear stress and flow mediated dilation of the artery, from data acquired from the obtained images;
(h) determining a relationship between wall shear stress and flow mediated dilation;
(i) determining if the relationship between wall shear stress and flow mediated dilation is in a range of normal individuals and
(j) determining if the relationship between wall shear stress and flow mediated dilation is outside the range of normal individuals, whereby a relationship outside the range is indicative of abnormal vascular endothelial function.
An additional preferred method of the invention include methods determining arterial wall shear stress during hyperemic response, wherein steps of obtaining images of an artery prior to, during, and following occlusion of the artery are identical to those of the abovementioned method, and further comprise steps of determining indicators of vascular endothelial function such as wall shear stress throughout the process of occlusion and resulting hyperemia, from calculations using data generated through obtained images.
An additional preferred aspect of the invention includes determination of a pattern of the time course of wall shear stress throughout the process of occlusion and resulting hyperemia and compare the pattern to one of normal individuals.
Another preferred method of the invention includes methods of determining a relationship between shear stress stimulus and dilation response during hyperemic response, wherein steps of obtaining images of an artery prior to, during, and following occlusion of the artery are identical to those of the abovementioned method, and further comprise steps of determining indicators of vascular endothelial function such as wall shear stress and flow mediated dilation from calculations using data generated from images, followed by determining a relationship between the obtained shear stress stimulus value or the change in wall shear stress as compared from baseline to peak hyperemia and the obtained dilation response value.
A further preferred method of the invention includes methods of determining a relationship between arterial diameter and hyperemic wall shear stress, wherein steps of obtaining images of an artery prior to, during, and following occlusion of the artery are identical to those of the abovementioned method; and further comprise steps of determining the artery diameter at baseline and the wall shear stress following release of occlusion from calculations using data generated from obtained images; and determining a relationship between the wall shear stress generated and the size of the artery.
Additionally provided are diagnostic methods of evaluating vascular endothelial functions of patients having cardiac risk factors, using the methods provided herein.
Other aspects and embodiments of the invention are discussed below.